Structural proteins of Kaposi’s sarcoma-associated herpesvirus antagonize p53-mediated apoptosis

Abstract

The tumor suppressor p53 is a central regulatory molecule of apoptosis and is commonly mutated in tumors. Kaposi's sarcoma-associated herpesvirus (KSHV)-related malignancies express wild-type p53. Accordingly, KSHV encodes proteins that counteract the cell death-inducing effects of p53. Here, the effects of all KSHV genes on the p53 signaling pathway were systematically analyzed using the reversely transfected cell microarray technology. With this approach we detected eight KSHV-encoded genes with potent p53 inhibiting activity in addition to the previously described inhibitory effects of KSHV genes ORF50, K10 and K10.5. Interestingly, the three most potent newly identified inhibitors were KSHV structural proteins, namely ORF22 (glycoprotein H), ORF25 (major capsid protein) and ORF64 (tegument protein). Validation of these results with a classical transfection approach showed that these proteins inhibited p53 signaling in a dose-dependent manner and that this effect could be reversed by small interfering RNA-mediated knockdown of the respective viral gene. All three genes inhibited p53-mediated apoptosis in response to Nutlin-3 treatment in non-infected and KSHV-infected cells. Addressing putative mechanisms, we could show that these proteins could also inhibit the transactivation of the promoters of apoptotic mediators of p53 such as BAX and PIG3. Altogether, we demonstrate for the first time that structural proteins of KSHV can counteract p53-induced apoptosis. These proteins are expressed in the late lytic phase of the viral life cycle and are incorporated into the KSHV virion. Accordingly, these genes may inhibit cell death in the productive and in the early entrance phase of KSHV infection.

Murine Gammaherpesvirus 68 LANA and SOX Homologs Counteract ATM-Driven p53 Activity during Lytic Viral Replication

“…Consistent with this notion, a number of GHV proteins inhibit p53 function when expressed in isolation, including v-IRF1, v-IRF3, v-IRF4, RTA, and LANA, as well as a number of viral structural proteins for KSHV and EBNA1 and EBNA3C for EBV (25)(26)(27)(28)(29)(30)(31)(32). However, whether p53 inhibition by these proteins (and other lytic cycle proteins) contributes to efficient viral replication is largely unexplored.…”

“…A screen of KSHV proteins identified RTA and several other viral proteins capable of repressing p53 transcriptional activity and cell death responses (30). Whether these viral proteins function to restrict p53 during lytic viral replication was not explored, and it is not yet known if MHV68 homologs exhibit similar functions.…”

KSHV latent protein LANA2 inhibits sumo2 modification of p53

“…LANA2 inhibits both the transcriptional activation and apoptosis induced by p53 through the inhibition of p53 phosphorylation, by altering its oligomerization and DNA-binding affinity, and by increasing its polyubiquitylation. [3][4][5][6][7][8] Apart from p53, LANA2 also compromises the activity of other tumor suppressors such as pRb or PML. 9,10 Interestingly, the control of these 2 tumor suppressors by LANA2 involves the regulation of their SUMO conjugation.…”

Immune control of oncogenic γ-herpesviruses

“…KSHV encodes several anti-apoptosis factors, including vBcl-2 [74], vFLIP [75], vIAP [74], K1 [76,77], vIRF4 [78], LANA [79] and miR-K10a [80]. Together, these viral factors target both the extrinsic and intrinsic apoptosis pathways.…”